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Variation in germination of Clostridium difficile clinical isolates correlates to disease severity.
Carlson PE, Kaiser AM, McColm SA, Bauer JM, Young VB, Aronoff DM, Hanna PC
(2015) Anaerobe 33: 64-70
MeSH Terms: Clostridium difficile, Enterocolitis, Pseudomembranous, Humans, Severity of Illness Index, Spores, Bacterial
Show Abstract · Added June 2, 2017
Over the past two decades, Clostridium difficile infections have been increasing in both number and severity throughout the world. As with other spore forming bacteria, germination is a vital step in the life cycle of this pathogen. Studies have examined differences in sporulation and toxin production among a number of C. difficile clinical isolates; however, few have examined differences in germination and the relationship between this phenotype and disease severity. Here, over 100 C. difficile isolates from the University of Michigan Health System were examined for overall germination in response to various combinations of known germinants (taurocholate) and co-germinants (glycine and histidine). Significant variation was observed among isolates under all conditions tested. Isolates representing ribotype 014-020, which was the most frequently isolated ribotype at our hospital, exhibited increased germination in the presence of taurocholate and glycine when compared to isolates representing other ribotypes. Interestingly, isolates that caused severe disease exhibited significantly lower germination in response to minimal germination conditions (taurocholate only), indicating increased control over germination in these isolates. These data provide a broad picture of C. difficile isolate germination and indicate a role for precise control of germination in disease severity.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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5 MeSH Terms
Infectious causes of necrotizing enterocolitis.
Coggins SA, Wynn JL, Weitkamp JH
(2015) Clin Perinatol 42: 133-54, ix
MeSH Terms: Bacterial Infections, Candidiasis, Enterocolitis, Necrotizing, Humans, Infant, Infant, Newborn, Infant, Premature, Virus Diseases
Show Abstract · Added October 16, 2015
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency among premature infants. Although a large body of research has focused on understanding its pathogenesis, the exact mechanism has not been elucidated. Of particular interest is the potential causative role of infectious culprits in the development of NEC. A variety of reports describe bacterial, viral, and fungal infections occurring in association with NEC; however, no single organism has emerged as being definitively involved in NEC pathogenesis. In this review, the authors summarize the literature on infectious causes of NEC.
Copyright © 2015 Elsevier Inc. All rights reserved.
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8 MeSH Terms
Postoperative burden of hospital-acquired Clostridium difficile infection.
Abdelsattar ZM, Krapohl G, Alrahmani L, Banerjee M, Krell RW, Wong SL, Campbell DA, Aronoff DM, Hendren S
(2015) Infect Control Hosp Epidemiol 36: 40-6
MeSH Terms: Academic Medical Centers, Adult, Age Factors, Aged, Amputation, Clostridium difficile, Digestive System Surgical Procedures, Emergency Service, Hospital, Endocrine Surgical Procedures, Enterocolitis, Pseudomembranous, Female, Gynecologic Surgical Procedures, Hospitals, Community, Humans, Hypoalbuminemia, Immunosuppression, Incidence, Length of Stay, Lower Extremity, Male, Middle Aged, Patient Readmission, Postoperative Complications, Preoperative Period, Prospective Studies, Risk Factors, Sepsis
Show Abstract · Added June 2, 2017
OBJECTIVE Clostridium difficile infection (CDI) is a common hospital-acquired infection. Previous reports on the incidence, risk factors, and impact of CDI on resources in the surgical population are limited. In this context, we study CDI across diverse surgical settings. METHODS We prospectively identified patients with laboratory-confirmed postoperative CDI after 40 different general, vascular, or gynecologic surgeries at 52 academic and community hospitals between July 2012 and September 2013. We used multivariable regression models to identify CDI risk factors and to determine the impact of CDI on resource utilization. RESULTS Of 35,363 patients, 179 (0.51%) developed postoperative CDI. The highest rates of CDI occurred after lower-extremity amputation (2.6%), followed by bowel resection or repair (0.9%) and gastric or esophageal operations (0.7%). Gynecologic and endocrine operations had the lowest rates (0.1% and 0%, respectively). By multivariable analyses, older age, chronic immunosuppression, hypoalbuminemia (≤3.5 g/dL), and preoperative sepsis were associated with CDI. Use of prophylactic antibiotics was not independently associated with CDI, neither was sex, body mass index (BMI), surgical priority, weight loss, or comorbid conditions. Three procedure groups had higher odds of postoperative CDI: lower-extremity amputations (adjusted odds ratio [aOR], 3.5; P=.03), gastric or esophageal operations (aOR, 2.1; P=.04), and bowel resection or repair (aOR, 2; P=.04). Postoperative CDI was independently associated with increased length of stay (mean, 13.7 d vs 4.5 d), emergency department presentations (18.9 vs 9.1%) and readmissions (38.9% vs 7.2%, all P<.001). CONCLUSIONS Incidence of postoperative CDI varies by surgical procedure. Postoperative CDI is also associated with higher rates of extended length of stay, emergency room presentations, and readmissions, which places a potentially preventable burden on hospital resources.
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27 MeSH Terms
CD8αα⁺ innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity.
Van Kaer L, Algood HMS, Singh K, Parekh VV, Greer MJ, Piazuelo MB, Weitkamp JH, Matta P, Chaturvedi R, Wilson KT, Olivares-Villagómez D
(2014) Immunity 41: 451-464
MeSH Terms: Animals, Antigen Presentation, CD8 Antigens, Citrobacter rodentium, Cytochalasin D, Enterocolitis, Necrotizing, Helicobacter pylori, Histocompatibility Antigens Class I, Humans, Immunity, Mucosal, Inhibitor of Differentiation Protein 2, Interleukin Receptor Common gamma Subunit, Interleukin-15, Interleukin-2, Interleukin-7, Intestinal Mucosa, Lymphocyte Activation, Lymphocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis
Show Abstract · Added January 20, 2015
Innate immune responses are critical for mucosal immunity. Here we describe an innate lymphocyte population, iCD8α cells, characterized by expression of CD8α homodimers. iCD8α cells exhibit innate functional characteristics such as the capacity to engulf and kill bacteria. Development of iCD8α cells depends on expression of interleukin-2 receptor γ chain (IL-2Rγc), IL-15, and the major histocompatibility complex (MHC) class Ib protein H2-T3, also known as the thymus leukemia antigen or TL. While lineage tracking experiments indicated that iCD8α cells have a lymphoid origin, their development was independent of the transcriptional suppressor Id2, suggesting that these cells do not belong to the family of innate lymphoid cells. Finally, we identified cells with a similar phenotype in humans, which were profoundly depleted in newborns with necrotizing enterocolitis. These findings suggest a critical role of iCD8α cells in immune responses associated with the intestinal epithelium.
Copyright © 2014 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis.
Weitkamp JH, Rosen MJ, Zhao Z, Koyama T, Geem D, Denning TL, Rock MT, Moore DJ, Halpern MD, Matta P, Denning PW
(2014) PLoS One 9: e99042
MeSH Terms: Animals, Cells, Cultured, Enterocolitis, Necrotizing, Female, Gene Expression Regulation, Humans, Infant, Newborn, Infant, Premature, Interleukin-17, Intestine, Small, Male, Mice, Mice, Inbred C57BL, Occludin, Receptors, Antigen, T-Cell, gamma-delta, T-Lymphocyte Subsets
Show Abstract · Added June 10, 2014
BACKGROUND - Gastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) γδ (γδ IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17.
OBJECTIVE - We sought to study the development of γδ IEL in the ileum of human infants and examine their role in NEC pathogenesis. We defined the ontogeny of γδ IEL proportions in murine and human intestine and subjected tcrδ-/- mice to experimental gut injury. In addition, we used polychromatic flow cytometry to calculate percentages of viable IEL (defined as CD3+ CD8+ CD103+ lymphocytes) and the fraction of γδ IEL in surgically resected tissue from infants with NEC and gestational age matched non-NEC surgical controls.
RESULTS - In human preterm infants, the proportion of IEL was reduced by 66% in 11 NEC ileum resections compared to 30 non-NEC controls (p<0.001). While γδ IEL dominated over conventional αβ IEL early in gestation in mice and in humans, γδ IEL were preferential decreased in the ileum of surgical NEC patients compared to non-NEC controls (50% reduction, p<0.05). Loss of IEL in human NEC was associated with downregulation of the Th17 transcription factor retinoic acid-related orphan nuclear hormone receptor C (RORC, p<0.001). TCRδ-deficient mice showed increased severity of experimental gut injury (p<0.05) with higher TNFα expression but downregulation of IL17A.
CONCLUSION - Complimentary mouse and human data suggest a role of γδ IEL in IL17 production and intestinal barrier production early in life. Specific loss of the γδ IEL fraction may contribute to NEC pathogenesis. Nutritional or pharmacological interventions to support γδ IEL maintenance in the developing small intestine could serve as novel strategies for NEC prevention.
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16 MeSH Terms
More than a gut feeling: predicting surgical necrotising enterocolitis.
Weitkamp JH
(2014) Gut 63: 1205-6
MeSH Terms: Algorithms, Biomarkers, Enterocolitis, Necrotizing, Female, Fibrinogen, Humans, Male, Peptides
Added February 27, 2014
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8 MeSH Terms
Abnormal heart rate characteristics before clinical diagnosis of necrotizing enterocolitis.
Stone ML, Tatum PM, Weitkamp JH, Mukherjee AB, Attridge J, McGahren ED, Rodgers BM, Lake DE, Moorman JR, Fairchild KD
(2013) J Perinatol 33: 847-50
MeSH Terms: Enterocolitis, Necrotizing, Environmental Monitoring, Female, Heart Rate, Humans, Infant, Newborn, Infant, Premature, Diseases, Male, Prospective Studies, Retrospective Studies
Show Abstract · Added February 27, 2014
OBJECTIVE - Earlier diagnosis and treatment of necrotizing enterocolitis (NEC) in preterm infants, before clinical deterioration, might improve outcomes. A monitor that measures abnormal heart rate characteristics (HRC) of decreased variability and transient decelerations was developed as an early warning system for sepsis. As NEC shares pathophysiologic features with sepsis, we tested the hypothesis that abnormal HRC occur before clinical diagnosis of NEC.
STUDY DESIGN - Retrospective review of Bells stage II to III NEC cases among infants <34 weeks gestation enrolled in a prospective randomized clinical trial of HRC monitoring at three neonatal intensive care units.
RESULT - Of 97 infants with NEC and HRC data, 33 underwent surgical intervention within 1 week of diagnosis. The baseline HRC index from 1 to 3 days before diagnosis was higher in patients who developed surgical vs medical NEC (2.06±1.98 vs 1.22±1.10, P=0.009). The HRC index increased significantly 16 h before the clinical diagnosis of surgical NEC and 6 h before medical NEC. At the time of clinical diagnosis, the HRC index was higher in patients with surgical vs medical NEC (3.3±2.2 vs 1.9±1.7, P<0.001).
CONCLUSION - Abnormal HRC occur before clinical diagnosis of NEC, suggesting that continuous HRC monitoring may facilitate earlier detection and treatment.
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10 MeSH Terms
Clostridium difficile Toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism.
Chumbler NM, Farrow MA, Lapierre LA, Franklin JL, Haslam DB, Haslam D, Goldenring JR, Lacy DB
(2012) PLoS Pathog 8: e1003072
MeSH Terms: Animals, Bacterial Proteins, Bacterial Toxins, Caco-2 Cells, Clostridium difficile, Enterocolitis, Pseudomembranous, Epithelial Cells, Female, HeLa Cells, Humans, Male, Mutation, Necrosis, Swine
Show Abstract · Added September 3, 2013
Clostridium difficile is the most common cause of antibiotic-associated nosocomial infection in the United States. C. difficile secretes two homologous toxins, TcdA and TcdB, which are responsible for the symptoms of C. difficile associated disease. The mechanism of toxin action includes an autoprocessing event where a cysteine protease domain (CPD) releases a glucosyltransferase domain (GTD) into the cytosol. The GTD acts to modify and inactivate Rho-family GTPases. The presumed importance of autoprocessing in toxicity, and the apparent specificity of the CPD active site make it, potentially, an attractive target for small molecule drug discovery. In the course of exploring this potential, we have discovered that both wild-type TcdB and TcdB mutants with impaired autoprocessing or glucosyltransferase activities are able to induce rapid, necrotic cell death in HeLa and Caco-2 epithelial cell lines. The concentrations required to induce this phenotype correlate with pathology in a porcine colonic explant model of epithelial damage. We conclude that autoprocessing and GTD release is not required for epithelial cell necrosis and that targeting the autoprocessing activity of TcdB for the development of novel therapeutics will not prevent the colonic tissue damage that occurs in C. difficile - associated disease.
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14 MeSH Terms
Smad7 inhibits autocrine expression of TGF-β2 in intestinal epithelial cells in baboon necrotizing enterocolitis.
Namachivayam K, Blanco CL, MohanKumar K, Jagadeeswaran R, Vasquez M, McGill-Vargas L, Garzon SA, Jain SK, Gill RK, Freitag NE, Weitkamp JH, Seidner SR, Maheshwari A
(2013) Am J Physiol Gastrointest Liver Physiol 304: G167-80
MeSH Terms: Animals, Autocrine Communication, Blotting, Western, Cell Line, Colon, DNA-Binding Proteins, Disease Models, Animal, Down-Regulation, Enterocolitis, Necrotizing, Gestational Age, Humans, Immunohistochemistry, Intestinal Mucosa, Intracellular Signaling Peptides and Proteins, Papio anubis, Papio cynocephalus, Premature Birth, Proto-Oncogene Proteins, Reverse Transcriptase Polymerase Chain Reaction, Smad7 Protein, Transfection, Transforming Growth Factor beta2
Show Abstract · Added February 27, 2014
Preterm infants may be at risk of necrotizing enterocolitis (NEC) due to deficiency of transforming growth factor-β 2 (TGF-β(2)) in the developing intestine. We hypothesized that low epithelial TGF-β(2) expression in preterm intestine and during NEC results from diminished autocrine induction of TGF-β(2) in these cells. Premature baboons delivered at 67% gestation were treated per current norms for human preterm infants. NEC was diagnosed by clinical and radiological findings. Inflammatory cytokines, TGF-β(2), Smad7, Ski, and strawberry notch N (SnoN)/Ski-like oncoprotein (SKIL) was measured using quantitative reverse transcriptase-polymerase chain reaction, immunoblots, and immunohistochemistry. Smad7 effects were examined in transfected IEC6 intestinal epithelial cells in vitro. Findings were validated in archived human tissue samples of NEC. NEC was recorded in seven premature baboons. Consistent with existing human data, premature baboon intestine expressed less TGF-β(2) than term intestine. TGF-β(2) expression was regulated in epithelial cells in an autocrine fashion, which was interrupted in the premature intestine and during NEC due to increased expression of Smad7. LPS increased Smad7 binding to the TGF-β(2) promoter and was associated with dimethylation of the lysine H3K9, a marker of transcriptional silencing, on the nucleosome of TGF-β(2). Increased Smad7 expression in preterm intestine was correlated with the deficiency of SnoN/SKIL, a repressor of the Smad7 promoter. Smad7 inhibits autocrine expression of TGF-β(2) in intestinal epithelial cells in the normal premature intestine and during NEC. Increased Smad7 expression in the developing intestine may be due to a developmental deficiency of the SnoN/SKIL oncoprotein.
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22 MeSH Terms
Pomegranate seed oil reduces intestinal damage in a rat model of necrotizing enterocolitis.
Coursodon-Boyiddle CF, Snarrenberg CL, Adkins-Rieck CK, Bassaganya-Riera J, Hontecillas R, Lawrence P, Brenna JT, Jouni ZE, Dvorak B
(2012) Am J Physiol Gastrointest Liver Physiol 303: G744-51
MeSH Terms: Animals, Animals, Newborn, Diet, Enterocolitis, Necrotizing, Female, Gene Expression Regulation, Ileum, Lipids, Mucin-2, Neuropeptides, Plant Oils, Pregnancy, Punicaceae, RNA, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Seeds, Trefoil Factor-3
Show Abstract · Added July 11, 2013
Pomegranate seed oil (PSO), which is the major source of conjugated linolenic acids such as punicic acid (PuA), exhibits strong anti-inflammatory properties. Necrotizing enterocolitis (NEC) is a devastating disease associated with severe and excessive intestinal inflammation. The aim of this study was to evaluate the effects of orally administered PSO on the development of NEC, intestinal epithelial proliferation, and cytokine regulation in a rat model of NEC. Premature rats were divided into three groups: dam fed (DF), formula-fed rats (FF), or rats fed with formula supplemented with 1.5% of PSO (FF + PSO). All groups were exposed to asphyxia/cold stress to induce NEC. Intestinal injury, epithelial cell proliferation, cytokine production, and trefoil factor 3 (Tff3) production were evaluated in the terminal ileum. Oral administration of PSO (FF+PSO) decreased the incidence of NEC from 61 to 26%. Feeding formula with PSO improved enterocyte proliferation in the site of injury. Increased levels of proinflammatory IL-6, IL-8, IL-12, IL-23, and TNF-α in the ileum of FF rats were normalized in PSO-treated animals. Tff3 production in the FF rats was reduced compared with DF but not further affected by the PSO. In conclusion, administration of PSO protects against NEC in the neonatal rat model. This protective effect is associated with an improvement of intestinal epithelial homeostasis and a strong anti-inflammatory effect of PSO on the developing intestinal mucosa.
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19 MeSH Terms